1. Field of the Invention
This invention concerns the synthesis of antibiotic compounds of the cephalosporin series.
Azetidinones and thiazolinoazetidinones are now well known as intermediates for preparing cephalosporins. A variety of synthetic routes have been published. In general, all of them proceed by first opening the 5-membered ring of a penicillin to form a thiazolinoazetidinone. The 5-membered ring of these compounds may be opened to form the corresponding azetidinone. Modifications are made to the group on the nitrogen atom of the azetidinone ring (whether fused or not) and the resulting compound is re-cyclized to form the desired cephalosporin. The following publications are representative of those which describe such processes: Belgian Pat. No. 864,321, Belgian Pat. No. 832,174, Belgian Pat. No. 862,793, Belgian Pat. No. 863,700, Belgian Pat. No. 863,998, U.S. Pat. No. 4,079,181, U.S. Pat. No. 4,013,653, U.S. Pat. No. 4,077,970, British Pat. Nos. 1,472,863 through 1,472,870, and U.S. Pat. No. 4,018,776.
2. Prior Art
Some previous publications show or suggest halogenation of the butenoate group on an azetidinone or thiazolinoazetidinone. Particular attention is given to Belgian Pat. No. 862,793, where such a halogenation is performed on a 3-methyl-2-but-3-enoate group. This patent, of May 2, 1978, however, teaches generally that bromine, chlorine or iodine atoms may be inserted with the use of free radical initiators. N-Bromosuccinimide in the presence of azobisisobutyronitrile is emphasized in the patent, although sulfuryl chloride and molecular chlorine are also used. The patent shows that the oxazolinoazetidinones which are its starting compounds frequently have the oxazoline ring opened by the halogenation step, and that the methylbutenoate group is isomerized so that a mixture of products is obtained.
Belgian Pat. No. 864,321 shows the chlorination of a similar group on an oxazolinoazetidinone by molecular chlorine and strong light. However, a second chlorine atom is also added on the 3-carbon atom.
U.S. Pat. No. 4,077,970 and British Pat. Nos. 1,472,863 through 1,472,870 suggest the halogenation of a methylbutenoate group on a thiazolinoazetidinone. However, the halogenations which these patents show cause the isomerization of the 3-butenoate group to a 2-butenoate group.